Erivedge ® (vismodegib) mechanism of action

1. Erivedge® (vismodegib) mechanism of action F. Hoffman-La Roche Ltd. CH-4070 Basel Switzerland Date of preparation: May 2013 GL/ERIV/1305/0013o

2. What is Erivedge® (vismodegib)? • Erivedge is a small-molecule, Hedgehog pathway inhibitor that binds to Smoothened (SMO), the Hedgehog signal transducer1–4 • Highly potent, selective inhibitor of SMO1–4 • Developed through drug discovery, lead optimisation programme5 • Antitumour activity shown in a murine medulloblastoma model3 • Non-linear pharmacokinetic profile, suitable for once-daily dosing6,7 • Erivedgeis indicated for the treatment of adult patients with:8 • Locally advanced basal cell carcinoma (BCC) inappropriate for surgery or radiotherapy • Symptomatic metastatic BCC 1. Epstein EH. Nature Rev Cancer 2008;8:743-754; 2. Von Hoff DD et al. N Engl J Med 2009;361:1164-1172; 3. Rudin CM et al. N Engl J Med 2009;361:1173-1178; 4. Graham RA et al. J Clin Oncol 2010;28(suppl):Abst e13009; 5. Robarge KD et al. Bioorg Med Chem Lett 2009;19:5576-5581; 6. LoRusso PM et al. Clin Cancer Res 2011;17:5774-5782; 7. LoRosso PM et al. Clin Cancer Res 2011;17:2502-2508; 8. Erivedge(vismodegib) Summary of Product Characteristics. Roche. May 2013

3. Discovery of the genetic components of the Hedgehog pathway in Drosophila • Hedgehog was discovered in a systematic screen for embryonic lethal mutants of the fruit fly Drosophila • Mutations in the Hedgehog gene alter the segment polarity of Drosophila larvae and lead to a spiky-haired phenotype Nüsslein-Volhard C et al. Nature 1980;287:795-801

4. Hedgehog signalling pathway is critical for normal embryonic development • The Hedgehog pathway is involved in cell growth and differentiation to control organ formation during normal embryonic development in humans • Hedgehog signalling regulates embryonic development, ensuring that tissues reach their correct size and location, maintaining tissue polarity and cellular content1 • In the skin, the Hedgehog pathway is critical for regulating hair follicle and sebaceous gland development2 • Hedgehog signalling normally remains inactive in most adult tissues3 1. Caro I et al. Clin Cancer Res 2010;16:3335-3339; 2. Chiang C et al. Dev Biol 1999;205:1-9; 3. Scales SJ et al. Trends Pharmacol Sci 2009;30:303-312

5. When the Hedgehog pathway is inactive Patched inhibits Smoothened activity Inhibition No intracellular signal transduction No target gene expression

6. When Hedgehog ligand activates the Hedgehog pathway the cell responds by activating expression of target genes Inhibition Target gene expression

7. Abnormal Hedgehog pathway signalling is important in the pathogenesis of certain types of cancer including BCC • Inappropriate reactivation of the Hedgehog pathway has been linked to several human cancers1 • In BCC, abnormal Hedgehog pathway signalling is the key molecular driver of the disease2-4 • More than 90% of BCCs have abnormal activation of Hedgehog pathway signalling4-8 • Most BCC tumours have either inactivating mutations in patched (PTCH) or, less commonly, activating mutations in SMO1,4,9,10 • 1. Scales SJ. Trends Pharmacol Sci 2009;30:303-312; 2. So P et al. Expert Opin Investig Drugs 2010;19:1099-1112; • 3. Hutchin ME et al. Genes Dev 2005;19;214-223; 4. Epstein EH. Nat Rev Cancer 2008;8:743-754; 5. Teh MT et al. Cancer Res 2005;65:8597-8603; • 6. Kallassy M et al. Cancer Res 1997;57:4731-4735; 7. Unden AB et al. Cancer Res 1997;57:2336-2340; 8. Reifenberger J et al. Cancer Res 1998;58:1798-1803; • 9. Caro I et al. Clin Cancer Res 2010;16:3335-3339; 10. Rudin CM. Cancer Prev Res 2010;3:1-3

8. Mutation-driven Hedgehog signalling is involved in BCC: Inactivating PTCH mutations Inhibition Target gene expression Tumour cell proliferation and/or cell survival

9. Mutation-driven Hedgehog signalling is involved in BCC: Activating SMO mutations Inhibition Target gene expression Tumour cell proliferation and/or cell survival

10. Erivedge® (vismodegib) inhibits SMO – the central mediator of Hedgehog pathway signalling Erivedge No intracellular signal transduction Inhibition No target gene expression Decreased tumour cell proliferation and increased apoptosis

11. Summary • Erivedge® (vismodegib) is a small molecule that inhibits the activity of SMO, a key component of the Hedgehog signalling pathway • The Hedgehog signalling pathway has a crucial role during normal human embryonic development, but remains inactive in most adult tissues • Abnormal activation of the Hedgehog signalling pathway plays a critical role in the pathogenesis and progression of certain cancer types, including BCC • Abnormal Hedgehog pathway signalling is the key molecular driver of BCC • Hedgehog pathway mutations, most commonly in PTCH, drive abnormal Hedgehog pathway signalling in BCC • More than 90% of BCCs have abnormal activation of Hedgehog pathway signalling • Erivedgeis a potent and selective SMO inhibitor and is indicated for patients with locally advanced BCC or symptomatic metastatic BCC